Field of the Invention
A major goal in the pharmacological arts has been the development of methods and compositions to facilitate the specific delivery of therapeutic and other agents to the appropriate cells and tissues that would benefit from such treatment, and the avoidance of the general physiological effects of the inappropriate delivery of such agents to other cells or tissues of the body. One common example of the need for such specificity is in the field of antiproliferative agent therapy for the treatment of skin diseases and disorders, in which the amount of a variety of antiproliferative agents to be safely administered topically or locally to a patient is limited by their systemic cytotoxic effects.
In addition, it is recognized in the medical arts that certain subcellular organelles are the sites of pharmacological action of certain drugs or are involved in the biological response to certain stimuli. Specific delivery of diagnostic or therapeutic compounds to such intracellular organelles is thus desirable to increase the specificity and effectiveness of such clinical diagnostic or therapeutic techniques. This invention provides polar lipid drug conjugates that target dermal, intradermal and infradermal structures in skin for delivery of therapeutic agents for the treatment of skin diseases and disorders.
A. Drug Targeting
It is desirable to increase the efficiency and specificity of administration of a therapeutic agent to the cells of the relevant tissues in a variety of pathological states. This is particularly important as relates to antiproliferative agents. Such agents typically have pleiotropic antibiotic and cytotoxic effects that damage or destroy uninvolved cells and tissues as well as cells and tissues comprising the pathological site. Thus, an efficient delivery system which would enable the delivery of such drugs specifically to the diseased or affected tissues cells would increase the efficacy of treatment and reduce the associated "side effects" of such drug treatments, and also serve to reduce morbidity and mortality associated with clinical administration of such drugs.
Numerous methods for enhancing the biological activity and the specificity of drug action have been proposed or attempted. To date, however, efficient or specific drug delivery remains to be predictably achieved.
An additional challenge in designing an appropriate drug delivery scheme is to include within the drug conjugate a functionality which could either accelerate or reduce the rate at which the drug is released upon arrival at the desired site. Such a functionality would be especially valuable if it allowed differential rates of drug release.
Medicinal salves and ointments for topical treatment purposes are known in the prior art for the treatment of a variety of pathological conditions. A multitude of pathological and other conditions have been treated by topical application of many classes of compounds in a variety of carriers, such as salves and ointments. However, carriers used in these conventional treatments are in no way specific for deposition of drugs, and suffer from non-specific deposition of the antiproliferative drug into both healthy and affected portions of the skin. Appropriate concentrations of topically-applied antiproliferative drugs, for example, are currently limited by the escape of the active agent(s) into the systemic circulation, with deleterious effects on other tissues and organs. An example of such a situation is the use of the drug methotrexate to treat psoriasis, where the amount of methotrexate that is capable of being topically applied is limited by hepato- and nephrotoxicity caused by systemic escape of the compound from the skin.
There remains a need in the art for an effective means for delivering biologically-active compounds, specifically drugs including antiproliferative drugs, to skin by topical administration of salves, ointments, and the like. Advantageous embodiments of such delivery means are formulated to efficiently deliver the biologically-active compound to the appropriate layer of the skin, while minimizing transit of the compound into the systemic circulation.